(a) Field of the Invention
This invention relates to novel tetrapeptide amides of Formula I that are useful in the treatment of hypertension.
Hypertension is a condition caused by any of a variety of functional abnormalities. For example, hypertension may be related to abnormalities in adrenergic, cholinergic, or neuromuscular interactions; in hormonal balance; or in kidney function, which malfunctions often are caused by abnormalities of the other systems. Treatment with drugs that are intended to act at some receptor site involved in one of the malfunctioning systems has frequently been the basis of therapy. For example, numerous neural receptor blockers are known to act as antihypertensive agents, and diuretics are commonly used to counteract the effects of fluid retention associated with kidney dysfunction. Each of these regimens, however, is associated with side effects often related to inadequate specificity. See generally L. S. Goodman and A. Gilman, eds. The Pharmacological Basis of Therapeutics (New York, 1975), Fifth Edition, Chaps. 26, 27, 28, 30, 33, 39, 40.
The renin-angiotensin system has been implicated in hypertension. See Goodman and Gilman, supra, pp. 630-637. The enzyme renin converts the plasma protein angiotensinogen to the essentially inactive decapeptide angiotensin I, which in turn is proteolytically converted by the so-called "converting enzyme" to the potently vasoactive octapeptide angiotensin II. Various peptidases further hydrolyze angiotensin II to essentially inactive peptide fragments. In addition to regulating blood pressure, angiotensin also stimulates the secretion of aldosterone and thus is intimately involved in regulating the sodium-potassium balance. Thus, inhibition of renin could be an important means of controlling high blood pressure. Certain short-chain peptide analogs of angiotensinogen segments have been reported to inhibit renin activity. K. Poulsen, J. Burton, and E. Haber, Biochemistry, 12, 3877-3882 (1973); J. Burton, K. Poulsen, and E. Haber, Biochemistry, 14, 3892-3898 (1975); J. Burton, R. J. Cody, Jr., A. J. Herd, and E. Haber, Proc. Natl. Acad. Sci. U.S.A., 77, 5476-5479 (1980). Peptide inhibitors of renin activity have also been reported to lower blood pressure in primates. See J. Burton, R. J. Cody, Jr., A. J. Herd, and E. Haber, Proc. Natl. Acad. Sci. U.S.A., 77, 5476-5479 (1980); R. J. Cody, J. Burton, G. Evin, K. Poulsen, J. A. Herd, and E. Haber, Biochem. Biophys. Res. Commun., 97, 230-235 (1980). The present invention provides peptide amides of shorter length which are renin inhibitors and exhibit antihypertensive activity.
(b) Prior Art
Certain N-adamantane-substituted tetrapeptide amides are known. U.S. Pat. No. 4,273,704, having the same assignee as the present invention, relates to analgesic tetrapeptide amides having optionally substituted tyrosine as the N-terminal amino acid residue. Although the tyrosine-containing compounds disclosed in the '704 patent have been discovered by the present inventors to exhibit renin inhibitory activity, the antihypertensive activity has not previously been disclosed for those compounds. Moreover, the compounds of the present invention exhibit significantly less analgesic activity than prior art compounds of the '704 patent, thus affording an unexpected separation of biological properties.